.alpha.-L-aspartyl-L-phenylalanine methyl ester (hereinafter abbreviated as .alpha.-APM) is a compound commonly referred to as "Aspartame". It has a sweetness approximately 200 times that of cane sugar and thus is in ever-increasing demand as a diet sweetening agent.
Numerous chemical preparation processes of .alpha.-APM have so far been disclosed. There may be cited a variety of processes, for example, (1) a process which comprises condensating the hydrochloride of aspartic acid anhydride and L-phenylalanine methyl ester (Japanese Patent Publication No. 40069/1976, etc.), (2) a process which comprises condensating N-protective aspartic acid anhydride and L-phenylalanine methyl ester followed by de-protection (Japanese Patent Laid-Open Nos. 1370/1971 and 113841/1976, etc.), (3) a process which comprises reacting N-protective aspartic acid-.beta.-benzyl ester with L-phenylalanine methyl ester in the presence of a condensating agent followed by de-protection (Japanese Patent Laid-Open No. 130846/1984) and (4) a process which comprises reacting N-carboxy-aspartic acid anhydride and L-phenylalanine methyl ester (Japanese Patent Laid-Open No. 96557/1973).
However, all of these processes employ L-phenylalanine methyl ester as one of the raw materials, requiring complex steps of methyl-esterification of L-phenylalanine prior to the reaction with the active derivatives of aspartic acid.
Moreover, further investigation has revealed that L-phenylalanine methyl ester is a compound in which its two free molecules in a solution are liable to condensate and cyclize to 2,5-dibenzyl-diketopiperazine. This face may be responsible for various disadvantages taking place in the industrial production of .alpha.-APM.
Accordingly, it is desirable to develop a process which is free of these disadvantages in the production of .alpha.-APM, i.e., a process in which L-phenylalanine methyl ester is not used as a raw material.
As a process for preparing .alpha.-APM which does not employ L-phenylalanine methyl ester, there has been disclosed a process for preparing .alpha.-APM which comprises condensating N-formyl aspartic acid anhydride with L-phenylalanine in glacial acetic acid to form N-formyl-.alpha.-L-aspartyl-L-phenylalanine, deformylating the N-formyl-.alpha.-L-aspartyl-L-phenylalanine to form .alpha.-L-aspartyl-L-phenylalanine, and esterifying said compound in methanol (Japanese Patent Publication No. 26133/1980), and a process in which the esterification step of .alpha.-L-aspartyl-L-phenylalanine to .alpha.-APM is improved (Japanese Patent Laid-Open No. 82752/1978).
However, since the former process brings about the estrification reaction in a substantailly non-aqueous solution, the reaction has practically no freedom of selectivity so that not only the intended esterification but also the estrification of its .beta.-carboxyl group of aspartic acid as well as the diesterification takes place to a large extent. Therefore, the process suffers such disadvantages as low yield of .alpha.-APM.
The latter process, which is established by improving the former process, bring about the methyl-esterification of .alpha.-L-aspartyl-L-phenylalanine in the presence of a considerable amount of water and the .alpha.-APM thus formed is deposited as its hydrochloride which is hardly soluble in the reaction system, thereby increasing the selectivity toward .alpha.-APM. However, the yield of isolation of .alpha.-APM in the latter process is at most 50-60% (based on .alpha.-L-aspartyl-L-phenylalanine) and thus is insufficient.
As another process in which L-phenylalanine methyl ester is not used, there has recently been disclosed a process for preparing .alpha.-APM which comprises condensating the N-carboxylic acid anhydride of L-aspartic acid-.beta.-methyl ester and L-phenylalanine to produce .alpha.-L-aspartyl-L-phenylalanine-.beta.-methyl ester and subjecting said compound to intramolecular transesterification in an aqueous hydrochloric acid solution containing methanol (Japanese Patent Laid-Open Nos. 225152/1984 and 225153/1984).
However, in this process, the esterification for producing L-aspartic acid-.beta.-methyl ester is poor in selectivity and thus is low in yield. Further, its N-carboxylic acid anhydride, which is produced by reacting L-aspartic acid-.beta.-methyl ester with phosgene, is liable to polymerize by being brought into contact with a base or by other causes. Therefore, this process is disadvantageous from the industrial viewpoint.
As has been described above, the conventional preparation processes of .alpha.-APM have several stages of complicated steps and have merits and demerits in the stability of its intermediates and in yield or in safety. Thus, it is the existing state of art that there are no efficient processes for preparing .alpha.-APM.
Further, a new preparation process of .alpha.-APM in which .alpha.-L-aspartyl-L-phenylalanine dimethyl ester is hydrolyzed in an aqueous methanol-hydrochloric acid solution has lately been disclosed (Japanses Patent Laid-Open No. 219258/1984). According to this disclosure, the starting .alpha.-L-aspartyl-L-phenylalanine dimethyl ester is prepared by de-formylatioun and estrification of N-formyl-.alpha.-L-aspartyl-L-phenylalanine methyl ester or by condensating the N-carboxylic acid anhydride of L-aspartic acid-.beta.-methyl ester with L-phenylalanine methyl ester. Thus, the process employs L-phenylalanine methyl ester for the preparation of the starting material and therefore involves the above-described problems.